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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
  • C07D239/12—Nitrogen atoms not forming part of a nitro radical
  • C07D239/16—Nitrogen atoms not forming part of a nitro radical acylated on said nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/44—Acylated amino or imino radicals
  • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to new guanidinothiazole derivatives containing alkylene bridges, a process for their preparation and their use as medicaments, in particular for influencing lipid metabolism, as antithrombotic agents and as antimycotic agents.
• the present invention relates to guanidinothiazole derivatives containing alkylene bridges, of the general formula (I) ##STR1## in their isomeric forms in which A represents an alkylene radical an optionally substituted by aryl, alkyl, aralkyl, hydroxy,
• R 1 and R 2 can be identical or different and represent hydrogen or optionally substituted alkyl
• R 3 represents hydrogen, optionally substituted alkyl, optionally substituted aryl, carbalkoxy, carbaryloxy or carboxamide and
• R 4 represents hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, e.g. furyl, pyridyl, thienyl, optionally substituted alkenyl, carbalkoxy, carbaryloxy, carbooxamide or the radical ##STR2## but R 3 and R 4 do not simultaneously denote hydrogen, and their physiologically acceptable salts with inorganic and organic acids and bases.
• the present invention preferably relates to guanidinothiazole derivatives containing alkylene bridges, of the above general formula (I), in which
• A represents an optionally substituted alkylene radical with preferably 2 to 4 carbon atoms in the chain
• R 1 and R 2 can be identical or different and represent hydrogen or optionally substituted lower alkyl, preferably with 1 to 4 C atoms,
• R 3 represents hydrogen, or represents alkyl with 1-4 carbon atoms which is optionally substituted by hydroxyl, alkoxy, alkylthio, lower alkylcarbonyloxy or carbalkoxy, or represents aryl, in particular phenyl, the phenyl radical being optionally monosubstituted, disubstituted or polysubstituted by identical or different substituents from the group comprising alkyl with 1-4 carbon atoms, halogen, hydroxyl, alkoxy, alkylthio, amino and nitro, or represents carbalkoxy, in particular carbomethoxy, carbethoxy or carbocyclohexyloxy, or represents carbaryloxy, for example carbophenoxy, or represents carboxamide, in particular carboxamide in which the amide group is substituted by optionally substituted aryl or alkyl with 1-20 carbon atoms, and
• R 4 represents hydrogen, or represents straight-chain, branched or cyclic alkyl with 1-10 carbon atoms which is optionally substituted by hydroxyl, alkoxy, alkylthio, optionally substituted aryloxy or arylthio, halogen, carbalkoxy, carboxamide or cyano, or represents aryl, in particular phenyl, biphenyl, naphthyl, tetrahydronaphthyl or indanyl, which is optionally monosubstituted or polysubstituted by identical or different substituents from the group comprising straight-chain, branched or cyclic alkyl with 1-10 carbon atoms, hydroxyl, alkoxy, halogen, amino and nitro, or represents heteroaryl, in particular optionally substituted furyl or thienyl, or represents alkenyl which is optionally substituted by lower alkyl, aryl or carbalkoxy, or represents carbalkoxy, in particular carbalkoxy in which
• alkyl refers preferably to groupings containing 1 to 10, especially 1 to 4 and particularly 1 or 2 carbon atoms; the term “aryl” (taken either per se or as a portion of a moiety, e.g.
• aralkyl refers preferably to mono- or bi-cyclic carbocyclic aryl; the term “heteroaryl” refers preferably to groupings containing oxygen, nitrogen or sulfur atoms as hetero atoms, such as pyridine, thiophane, etc.; the term “alkenyl” preferably contains up to 8 and particularly up to 3 or 4 carbon atoms; the term “halogen” preferably refers to chlorine, bromine or fluorine; the term “cycloalkyl” preferably refers to cycloalkyl having 3 to 7 ring members, preferably cyclopentyl and cyclohexyl.
• guanidinothiazole derivatives containing alkylene bridges of the above formula (I) are those which are listed in Table (I) and have the substituents shown in Table (I).
• guanidinothiazole derivatives according to the invention which contain alkylene bridges and are of the formula (I), are synthesised in accordance with the following equations: ##STR3##
• the cyclic N-cyanoguanidines of the general formula (IV) are obtained in a manner which is in itself known [compare C. M. Baltzer and C. G. MacCarty, J. Org. Chem. 38, 155 (1973); DT-OS (German Published Specification) No. 2,205,745] by reacting alkylenediamines (II) with S,S 1 -dimethyl N-cyanoimidodithiocarbonate (III).
• Guanylthiourea is obtained by addition of hydrogen sulphide onto N-cyanoguanidine [compare Org. Synth. Coll. Volume IV, 502].
• the guanylthioureas containing N,N 1 -alkylene bridges (VI) are obtained in an analogous manner from the cyclic N-cyanoguanidines (IV).
• the solvents used in this reaction are water and protic and aprotic organic solvents, for example ethanol, dimethylformamide or pyridine, and mixtures of the solvents.
• the reaction is carried out at a temperature of 0°-150° C., preferably at 20°-120° C.
• Diluents which are used in this reaction are organic solvents and water.
• Preferred solvents are water, aromatic and heteroaromatic hydrocarbons, of which toluene and pyridine are particularly preferred, ketones, for example acetone, and alcohols, for example ethanol.
• the reaction temperatures can be varied within a substantial range.
• the reaction is generally carried out between about 0° C. and 180° C., preferably between room temperature and the boiling point of the particular diluent.
• the reaction time depends on the temperature and the diluent and is between 0.5 and 24 hours.
• the free guanidinothiazole derivatives containing alkylene bridges (I) can be liberated from the salts of the compounds [(I)xHX] according to the invention with bases.
• bases Alkali metal and alkaline earth metal carbonates, bicarbonates and hydroxides and ammonia and organic bases, such as tertiary aliphatic and aromatic amines, are preferably used.
• Water is preferably employed as the diluent.
• Particularly preferred new active compounds are the compounds of formula I specifically listed in Table 1, which active compounds are prepared using procedures analogous to those described infra under "Preparation examples”.
• the compounds of Examples 18, 19, 20 and 21 in Table I can be prepared from the compound of Example 11 by reaction with corresponding nucleophiles, such as 2,4-dichlorophenol, thiophenol, imidazole and triazole.
• nucleophiles such as 2,4-dichlorophenol, thiophenol, imidazole and triazole.
• Examples 56 and 57 can also be obtained starting from the compound of Example 45 by reaction with, for example, ##STR60## wherein R 1 denotes alkyl or aryl.
• platelet aggregation-inhibiting medicaments as antithrombotic agents can meanwhile be regarded as a recognised therapy principle.
• the participation of platelets in atherosclerotic processes is also known, so that substances which have these properties and are to be used in the said indications are to be evaluated as advantageous.
• the minimum effective active compound concentration which inhibits platelet aggregation in the corresponding PRP samples is given.
• 0.8 ml of PRP and 0.1 ml of the active compound solution were pre-incubated in a water bath at 37° C.
• the platelet aggregation was then determined by the turbidometric method (Born, G. V. R.: J. Physiol. 162, 67, 1962) in an aggregometer at 37° C. (Seuter, F.: Haemostasis 5, 85-95, 1976).
• 0.1 ml of an aggregation-inducing collagen suspension was added to the pre-incubated sample.
• the change in optical density of the sample of PRP was recorded over a period of 6 minutes and was determined via the reading after 6 minutes. The percentage inhibition is calculated from the corresponding readings.
• the platelet aggregation was also determined in the context of the thromboatherosclerosis experiment.
• the active substance was administered to the animals orally in a Tylose suspension over a period of 10 days. On the 10th day, the animals were exsanguinated 90 minutes after the oral administration of the substance, and the PRP was isolated by means of centrifugation. After the PRP has been isolated, in vitro measurement of the aggregation inhibition starts, analogously to the process which has been described for the in vitro experiments; but without pre-incubation of the samples. 3 parts of rat PRP were also diluted with one part of physiological saline solution.
• Arteriosclerosis or atherosclerosis in the narrower sense, is a very complex disease in which it is possible to observe the participation of at least 3 main processes: 1. vascular wall damage with subsequent proliferation of its smooth muscle cells and formation of a fibromusculoelastic lesion; 2. lipid deposits; 3. mural clot formation and deposition thereof in the vascular wall. In the past, varying significance has been placed on these factors, which has led to the "thrombogenic” and "lipid infiltration” theory.
• thromboatherosclerosis model Because of some fluid transitions between atherosclerosis and thrombosis, we have called the method used "thromboatherosclerosis model".
• Literature Seuter, F., Sitt, R. and Busse, W. D., Experimentally induced thromboatherosclerosis. Folia angiologica 28, 85 (1980).
• Atherosclerotic plaques are induced in rats by combination of two noxae (risk factors), that is to say vascular lesion and hyperlipaemia.
• risk factors that is to say vascular lesion and hyperlipaemia.
• supercooling of the arteria carotis comm. (2 minutes, -10° C.)
• partial or complete endothelial scaling occurs in a locally restricted area.
• Proliferation of the intima occurs within 10 days, which is a relatively short period for such experiments, and largely corresponds to the early stages of atherosclerotic plaques in humans.
• the proliferation zones are removed and weighed.
• the moist weight in the supercooled segment of 1 cm is about 200-300 ⁇ g.
• the animals are additionally given a high-fat diet having the following composition:
• the lipid deposits are stained with the fat-soluble dyestuff Sudan IV and can be determined as an additional parameter.
• heparin In addition to alkylating cytostatic agents and glucocorticoids, which inhibit cell proliferation nonspecifically, only heparin has hitherto been effective in this model following parenteral administration. Lipid-lowering substances, such as cholestyramine, neomycin, nicotinic acid and the like were ineffective. The dose-dependent action of heparin, which serves as a positive reference standard in all experiments, has been described (Sitt, R., Seuter, F. and Busse, W. D., Suppression by Heparin of intimal proliferation in the injured carotid artery (rat). Arch Pharmacol., Suppl. 311, Abstr. 188, 1980).
• the scheme clearly shows that the therapy of vascular diseases by intervention in arachidonic acid metabolism can be carried out particularly effectively by substances which do not intervene only at one site in the metabolism of arachidonic acid, but have a profile of inhibiting or promoting effects on the individual metabolism steps.
• the lipid peroxides formed by the lipoxygenase degradation route are of importance in inflammation reactions. However, there are indications that these peroxides also participate in the formation of thromboses and the causing of endothelial damage. A blockade in the lipoxygenase path of the arachidonic acid metabolism could accordingly be a further desirable property.
• Certain lipid peroxides such as HPETE, generally have a cell-damaging action and appear to cause (irreversible) contractures of smooth muscle cells (vessels).
• 3 H-arachidonic acid is converted into the products of the cyclooxygenase/thromboxane synthetase path, in particular thromboxane A 2 , and those of the lipoxygenase path, HETE. Separation of the resulting products by thin layer chromatography gives a characteristic pattern. Inhibitors of the individual enzymatic reactions modify this pattern in a typical manner (Bailey, J. M. et al., Prostaglandins 13, 479-492 (1977)). The action of the compounds according to the invention on individual reactions in arachidonic acid metabolism are shown in Table 2.
• the compounds according to the invention are suitable, for example, for treating or preventing cardiac infarctions, angina pectoris, thromboembolic diseases in the venous and arterial region (postoperatively, transitorially ischaemic attacks, amaurosis fugax and the like) and other vascular syndromes, such as arteriosclerosis.
• guanidinothiazoles, with alkylene bridges, according to the invention display a surprising antifungal action against dermatophytes, yeasts and moulds.
• the in vitro tests were carried out in a series dilution test using germ inocula of on average 5 ⁇ 10 4 germs/ml of substrate.
• the nutrient medium used was
• the incubation temperature was 20° C. and the incubation time was 24 to 96 hours for yeasts and 96 hours for dermatophytes and moulds.
• Cholesterol and the substance to be tested were simultaneously administered orally in 0.75% strength tragacanth suspension. After 24 hours, the animals were sacrificed and the cholesterol content of the liver was determined. Cholesterol was determined by the Liebermann-Burchard method using the test combination of Boehringer Mannheim. Control animals received a corresponding volume of cholesterol/tragacanth suspension without the test substance. To monitor the rise in cholesterol as a result of cholesterol loading, tragacanth suspension containing no cholesterol was administered orally to another control group.
• Compound (f) corresponds to the guanidinothiazole (33) containing alkylene bridges in Table I.

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• 1982
  • 1982-05-28 DE DE19823220118 patent/DE3220118A1/de not_active Withdrawn
• 1983
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